Maleate salts of a quinazoline derivative useful as an antiangiogenic agent

Abstract

The present invention relates to AZD2171 maleate salt, to particular crystalline forms of AZD2171 maleate salt, to processes for their preparation, to pharmaceutical compositions containing them as active ingredient, to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans, and to their use in methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability.

The invention claimed is: 
     
       1. A maleate salt of 4-((-fluoro-2-methyl-1H-indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline in a Form A crystalline form, wherein the salt has at least three XRPD peaks selected from 21.5, 16.4 and 24.4 degrees theta. 
     
     
       2. A maleate salt of b  4 -((-fluoro-2-methyl-1H-indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline in a Form B crystalline form, wherein the salt has at least three XRPD peaks selected from 24.2, 22.7 and 15.7 degrees theta. 
     
     
       3. The maleate salt according to  claim 1 , wherein the salt has XRPD peaks selected from 21.5, 16.4, 24.4, 20.7, 25.0, 16.9, 12.1, 22.2, 17.4 and 17.6 degrees theta. 
     
     
       4. The maleate salt according to  claim 1 , wherein the salt has an XRPD pattern substantially the same as the XRPD pattern shown in  FIG. 5 . 
     
     
       5. The maleate salt according to  claim 2 , wherein the salt has XRPD peaks selected from 24.2, 22.7, 15.7, 12.0, 27.1, 25.0, 17.7, 15.0, 23.1 and 12.6 degrees theta. 
     
     
       6. The maleate salt according to  claim 2 , wherein the salt has an XRPD pattern substantially the same as the XRPD pattern shown in  FIG. 8 . 
     
     
       7. A pharmaceutical composition comprising the maleate salt according to  claim 1  in association with a pharmaceutically acceptable excipient or carrier. 
     
     
       8. A pharmaceutical composition comprising the maleate salt according to  claim 2  in association with a pharmaceutically acceptable excipient or carrier. 
     
     
       9. A process for the preparation of the maleate salt according to  claim 1 , which comprises:
 (i) dissolving 4-((-fluoro-2-methyl-1H-indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline free base in an organic solvent to form a solution; 
 (ii) adding an aqueous solution of maleic acid or adding a solution of maleic acid in an organic solvent; 
 (iii) allowing spontaneous nucleation to occur; 
 (iv) slurrying the resulting maleate salt of 4-((-fluoro-2-methyl-1H-indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline in a solvent until all the maleate salt is of Form A; and 
 (v) isolating the Form A maleate salt. 
 
     
     
       10. A process for the preparation of the maleate salt according to  claim 1 , which comprises:
 (i) dissolving 4-((-fluoro-2-methyl-1H-indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline free base in an organic solvent to form a solution; 
 (ii) adding an aqueous solution of maleic acid or adding a solution of maleic acid in an organic solvent; 
 (iii) obtaining a solution and adding a seed of the Form A maleate salt to initiate crystallisation; and 
 (iv) isolating the Form A maleate salt so formed as a crystalline solid. 
 
     
     
       11. A process for the preparation of the maleate salt according to  claim 2 , which comprises:
 (i) dissolving 4-((-fluoro-2-methyl-1H-indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline maleate salt in an organic solvent to form a solution; 
 (ii) adding the solution to a solvent in which the 4-((-fluoro-2-methyl-1H-indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline maleate salt has a lower solubility than it does in NMP, which results in crystallization of the Form B maleate salt; and 
 (iii) isolating the Form B maleate salt as a crystalline solid.